Apparatus and method for “LEPARS” interval-based fusion pacing

ABSTRACT

Efficient provision of hemodynamic benefits and therapy for patients suffering from intraventricular conduction delays or conduction blockage. By effectively measuring conduction delay or block (e.g., left bundle branch block or “LBBB”) and enhancing delivery of a novel form of left ventricle-only cardiac resynchronization therapy. Accordingly, a single LV fusion pacing stimulus is triggered from an atrial event (e.g., intrinsic or evoked depolarization). The triggering event can emanate from the right atrium (RA) or the left atrium (LA). The single LV fusion pacing stimulus is delivered prior to the intrinsic depolarization of the RV—upon expiration of a “LEPARS interval”—thus efficiently providing intraventricular electromechanical synchrony by fusion. During variations in heart rate the operating AV interval (herein A-LVp interval) is varied while the LEPARS interval is substantially essentially constant, thereby preserving the enhanced hemodynamics resulting from the fusion depolarization.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application relates to a non-provisional U.S. patentapplication by Hill; namely, Ser. No. 10/000,474 filed 26 Oct. 2001,issued 22 Mar. 2005 as U.S. Pat. No. 6,871,096 and entitled, “SYSTEM ANDMETHOD FOR BI-VENTRICULAR FUSION PACING” a non-provisional U.S. patentapplication by Burnes and Mullen entitled, “APPARATUS AND METHODS OFATRIAL-BASED BI-VENTRICULAR FUSION PACING;” Ser. No. 10/803,570 filed 17Mar. 2004 now U.S. Pat. No. 7,181,284 and a non-provisional U.S. patentapplication by B. Ferek-Petric; namely Ser. No. 10/802,953 filed 17 Mar.2004, entitled, “MECHANICAL SENSING SYSTEM FOR CARDIAC PACING AND/OR FORCARDIAC RESYNCHRONIZATION THERAPY,” now abandoned and the entirecontents of each is hereby incorporated by reference herein.

FIELD OF THE INVENTION

The present invention pertains to cardiac pacing systems. In particular,the invention relates to apparatus and methods for improving cardiacfunction for patients by employing an improved form of left ventricle(LV) pacing therapy delivery based at least in part on the premise thatRV activation via the right bundle is superior to RV pacing activation,and also utilizes the unique physiologic inter-ventricular conductiontime (IVCT) of a subject.

BACKGROUND OF THE INVENTION

Cardiac resynchronization therapy (CRT) is a promising and accepteddevice therapy for patients with systolic heart failure classified inNew York Heart Association (NYHA) class III and IV. Current (2003)indications include patients who, despite optimal medication, aresymptomatic, and who demonstrate LV asynchrony. The latter occurs inpatients with left bundle branch block (LBBB) and typically presentswith a QRS width (measured on an ECG machine) of greater than about130-150 ms. Herein, “asynchrony” is characterized by a delay in systoliccontraction between the intraventricular septum and the left ventricular(LV) free wall.

Currently available CRT bi-ventricular pacing generally employs one leadpositioned in operative communication with the right ventricle (RV) andone lead in operative communication with a portion of one of thetributaries of the coronary venous system. The myocardial venous systemprovides a pathway for deployment of LV stimulation of the lead (andassociated electrodes) to operatively communicate with the LV. In mostpatients, an additional lead is deployed to the right atrium (RA) foratrioventricular (AV) synchronization during pacing. Exceptions forplacement of the atrial lead include patients suffering from chronicatrial fibrillation (AF) or having a relatively high AF “burden.”According to such CRT delivery, electrical stimulation of both the RVand LV operates to assist ventricular asynchrony and increasecontractility (as measured by ventricular pressure development (dP/dt).For certain patients, further assistance of contractility can beachieved by variation of the inter-ventricular (“V-V”) interval. The V-Vinterval is the interval of time between LV and RV stimulation (or viceversa), which is a programmable parameter in currently available pulsegenerators (implantable, temporary and/or external). Optimization of theV-V interval can be performed on the guidance of echocardiographic orhemodynamic parameters as is known in the art.

In several studies it has been observed that LV pacing ishemodynamically superior or at least equal to bi-ventricular pacing.However, the inventors suggest that to date little or no attention hasbeen paid to the mechanism(s) behind the observation.

In the above-referenced patent application to Hill, Hill appears to havediscovered that in certain patients exhibiting symptoms resulting fromcongestive heart failure (CHF), cardiac output is enhanced by timing thedelivery of an LV pacing pulse such that evoked depolarization of the LVis triggered by a sensed intrinsic depolarization of the RV. Theconclusion was based on the notion that a “fusion” depolarizationenhances cardiac output in cardiac patients where the RV depolarizesfirst due to intact A-V conduction of a preceding intrinsic or evokedatrial depolarization wave front, but the A-V conducted depolarizationof the LV is unduly delayed. The fusion depolarization of the LV isattained by timing the delivery of an LV-PACE pulse to follow, in time,the intrinsic depolarization of the RV but to precede, in time, theintrinsic depolarization of the LV. Accordingly, an RV-PACE pulse is notdelivered due to the inhibition of the RV-PACE upon the occurrence of asensed RV-EVENT, allowing natural propagation of the wave front anddepolarization of the septum, while an LV-PACE pulse is prematurelydelivered in fusion with the RV depolarization.

However, due to a number of factors (e.g., the amount of time requiredfor appropriate signal processing, confounding conduction delays orconduction blockage of a patient, electrode placement and the like) fora variety of patients A CRT delivery system that takes all these factorsinto consideration is needed.

Specifically, there is a need for structures, methods and processes toefficiently and chronically deliver and control of pacing therapy toeffect ventricular fusion in cardiac patients who might otherwise notreceive similar benefits from bi-ventricular CRT therapy.

SUMMARY

The present invention relates to a novel means of determining theappropriate timing for LV-only pacing therapy delivery based on anevaluation of inter-ventricular conduction time (IVCT) between the RVand the LV. The inventors have empirically shown that LV hemodynamicresponse to LV-only ventricular pacing stimulation rivals LV hemodynamicresponse to bi-ventricular pacing (including CRT) for a majority ofpatients. According to the invention, ventricular fusion is achievedwhen a depolarization wavefront evoked by LV-only pacing merges with anintrinsic depolarization wavefront (propagated via the right bundlebranch). Fusion between this pair of depolarization wavefronts (oneintrinsically activated, one activated via pacing stimulus) is achievedby closely monitoring and maintaining the IVCT by adjustment of the AVinterval (for A-LV pacing).

The optimum value for what the inventors' refer to as the “LEPARSinterval” (derived from: LEft ventricular PAcing, Right ventricularSensing) can be determined acutely at the time an implantable pulsegenerator (IPG) is implanted. Thereafter, the operative AV interval canbe automatically adjusted pursuant to an algorithm intended to keep theLEPARS interval constant.

In one embodiment of the present invention, a data set optionallyconfigured as a look-up-table (LUT) correlates a plurality of data; forexample, LEPARS intervals, heart rates, activity sensor signal inputs,discrete physiologic cardiac timing intervals and the like. Dynamicallyreferencing the data set (e.g., LUT) set an appropriate operating AVdelay interval. If a mathematical derivation of heart rate is used toset the LEPARS interval, the data set or a lookup table can comprise atleast two data sets or LUTs, one for stable or relatively stable HR, andanother for various rate-of-change of the HR to more accurately reflecta physiologic LEPARS interval. Alternatively, the LEPARS pacing modalityaccording to the invention may be terminated in the event of relativelyhigh or unstable heart rates. In fact, the inventors suggest that theLEPARS pacing modality cease and/or a pacing mode switch is performed toa non-atrial tracking mode in the event that an arrhythmia is detected(esp. atrial fibrillation or “AF”). More generally, multiple LUTs may beutilized that correlate to one or more physiologic parameters (e.g.,containing AV intervals for both paced and intrinsic atrial activation).That is, the data set should provide operating AV intervals thatmaintain the LEPARS interval (i.e., the elapsed time between an LVpevent and the resulting RVs event) over a broad range of heart rates.

Among other aspects, the present invention provides an energy-efficientmanner of providing fusion-pacing therapy providing immediate improvedcontractility and maximum (LV) pressure development. A pacing stimulusis provided to the LV as is known in the art (e.g., via an electrodedeployed into a portion of the coronary sinus, great vein, and branchesthereof or epicardially) and the time interval (LEPARS interval) betweenLV pacing delivery and sensed depolarization of the RV is maintained. Asdepicted herein, an atrial pacing/sensing lead operatively couples to anatrial chamber, a pacing lead operatively couples to the LV, and asensing lead couples to the RV.

A variety of locations for the atrial lead can be used to successfullypractice the methods of the present invention. For example, electricalcommunication (e.g., pacing and sensing an atrial chamber) with the RAcan utilize a uni-polar or bi-polar electrode arrangement in either anepicardial or endocardial location. Similarly, depolarizations of theventricles can utilize any known sensing vector (e.g., tip-to-ring,coil-to-can, coil-to-coil, etc.). An endocardial location may includethe common RA pacing site of the RA appendage although RA septal orother locations are acceptable. An electrode operatively coupled to theLA may also be used, including such locations as the CS and portionsdistal to the os of the CS, as well as the inter-atrial septal wall,among others.

In addition, one or more mechanical, acoustic and/or activity sensorsmay be coupled to the heart and used to confirm that a desired amount ofventricular synchrony results from the fusion pacing therapy. Somerepresentative mechanical sensors for this purpose include fluidpressure sensors or acceleration sensors and the like. The mechanicalsensors operatively couple to the heart (e.g., LV lateral free-wall, RVseptal wall, epicardial RV locations, etc.). Output signals from suchsensors may be used to modify the timing of the fusion-pacing stimulus,especially during episodes such as a rapidly changing heart rate.

In addition to the therapy delivery aspects of the present invention, adiscrete few therapy delivery guidance or security options may be usedto determine if the fusion pacing therapy ought to be modified,initiated or discontinued. For example, in the event a transientconduction anomaly interrupting AV conduction is detected a pacingmodality switch to a double or triple chamber pacing modality could beimplemented (e.g., DDD). In the event that the LEPARS interval decreasesor increases relative to a prior calibrated or operating value a similarpacing mode switch can be implemented, fusion-pacing could cease or theAV interval adjusted. If one of the sensors indicates increasingventricular asynchrony or decreasing hemodynamic response to thetherapy, the fusion pacing therapy can be modified or cease.Furthermore, from time-to-time the fusion pacing therapy could besuspended while cardiac activity is monitored so that any change innormal sinus rhythm, or improvement in ventricular synchrony orperformance (e.g., desirable so-called “reverse remodeling”) can beaccommodated. In the event that ventricular synchrony and conductionimproves markedly, or that the suspension of fusion-based CRT results inimproved hemodynamics, a pacing mode switch from fusion-based CRT to avery energy efficient physiologic, single stimulus, atrial-based pacingmode such as AAI, ADI, AAI/R, ADI/R and the like may be implemented.Thereafter, in the event that conduction anomalies cause ventricularasynchrony and resultant hemodynamic compromise or a heart failuredecompensation event, another pacing mode switch can be implemented toresume an fusion-pacing mode according to the present invention.

The foregoing and other aspects and features of the present inventionwill be more readily understood from the following detailed descriptionof the embodiments thereof, when considered in conjunction with thedrawings, in which like reference numerals indicate similar structuresthroughout the several views.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of transmission of the cardiac depolarizationwaves through the heart in a normal intrinsic electrical activationsequence.

FIG. 2 is a schematic diagram depicting a three channel, atrial andbi-ventricular, pacing system for implementing the present invention.

FIG. 3 is a simplified block diagram of one embodiment of IPG circuitryand associated leads employed in the system of FIG. 2 for providingthree sensing channels and corresponding pacing channels thatselectively functions in an energy efficient ventricular-fusion pacingmode according to the present invention.

FIG. 4 is schematic representation of the basic principles of a LEPARSinterval-driven pacing modality according to the present invention.

FIG. 5 illustrates four cardiac cycles during which different AVintervals were applied, said AV intervals composed of atrial pacing (AP)and LV pacing (VP) events and the resulting EGM waveforms of the evokedresponses.

FIG. 6 depicts RV and LV QRS complex morphology during RV and LV pacingat AV intervals ranging from 40 ms to 200 ms.

FIG. 7 is a temporal tracing of a surface ECG, a pacing “marker channel”composed of atrial pacing events (AP), LV pacing events (VP), and RVsensing events (VR)—because such events are deemed non-physiologic“refractory” events occurring too soon after the VP events, andresulting LV pressure development (dP/dt_(max)).

FIG. 8 graphically depicts a comparison of percentage increase inpressure development (“% increase dP/dt”) for LV-only pacing therapydelivery at AV₇₅ to 35 patients (the 22 developed fusion and the 13 thatdid not).

FIGS. 9A and 9B graphically depicts comparison of pressure development(dP/dt) for LV-only pacing and bi-ventricular pacing at two different AVintervals (AV₁₀₀ and AV₇₅).

FIGS. 10-12 are flow charts depicting a few embodiments and/or aspectsof the present invention.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

In a prior study for the optimization of AV and V-V intervals,development of pressure in the LV (e.g., dP/dt) for a triple-chamber IPGwas utilized as a hemodynamic parameter reflecting LV contractility. Inone protocol, a measurement of dP/dt during RV-only pacing was studied(as function of the AV interval). Observation at the time yielded aconclusion that a 100 ms AV interval (ARV₀₀) is the longest AV intervalat which no (electrocardiographic-based as opposed tomechanically-based) ventricular fusion occurred during RV-only pacing.Subsequently the effect of an AV interval of 75%, 50% and 25% of thelongest value was measured (in the drawings appended hereto referred toas AV₇₅, AV₅₀, and ALV25₅ respectively). After these measurements weremade the protocol was continued with LV-only pacing employing the sameAV intervals. Surprisingly, fusion was not observed during RV-onlypacing, whereas fusion was observed during LV pacing (at ARV₀₀ and in60% of the patients at AV₇₅). The QRS tracings depicting the presence offusion is presented in FIG. 6 (wherein an ECG lead (RV) shows ORSmorphology during delivery of RV-only and LV-only pacing therapy).During RV pacing no fusion was observed and during LV-only pacing fusionwas observed to be present for AV intervals of 120 ms to 180 ms (see EGMtraces 672,674,676 of FIG. 6).

FIG. 9A depicts a comparison 900 of developing pressure (dP/dt) withbi-ventricular pacing versus LV-only ventricular pacing at two AVintervals (ARV₀₀ and AV₇₅). Inspection of FIG. 9A illustrates superiorhemodynamic effects of the inventive fusion therapy according to thepresent invention (e.g., higher dP/dt_(max) for LV pacing—of about 979mmHg/s—than for bi-ventricular pacing—of about 949 mmHg/s) which ishighly statistically significant (p=0.006). Assuming that fusion isachieved and maintained for a range of operating AV intervals, thehemodynamics of LV fusion according to the invention are believed to besuperior to bi-ventricular pacing therapy. With reference to FIG. 8,(wherein an AV interval that produced fusion in response to LV-onlypacing in all patients is referred to as AV₁₀₀) an AV interval of 75% ofthe maximum (denoted AV₇₅) produced LV-only fusion depolarization forjust over 60% of the patients during LV-only pacing. That is, thepercentage of patients with fusion at AV₇₅ is illustrated in FIG. 8(22/35=63%). Referring again to FIG. 9A, the comparison illustrates thatat AV₇₅, LV pacing shows a trend towards a higher pressurerate-of-change (dP/dt) than bi-ventricular pacing (i.e., dP/dt_(max) forLV pacing was 902 mmHg/s while for biventricular pacing the value was888 mmHg/s). Turning now to FIG. 9B illustrates at 901 maximum pressuredevelopment (dP/dt_(max)) at AV₇₅ for patients that achieved LV-onlypacing fusion and those that did not achieve fusion. Inspection of FIG.9A reveals the following: of the 22 patients that achieved LV-onlypacing fusion showed a trend towards a higher dP/dt_(max) (as depictedat 912) than they did when receiving bi-ventricular pacing (as depictedat 914) of 964 mmHg/s versus 938 mmHg/s. In contrast, patients who didnot achieve LV-only pacing fusion fared poorly when compared to pressuredevelopment from bi-ventricular pacing (919 mmHg/s vs. 957 mmHg/s) asdepicted at 916,918.

The inventors thus posit that LV-only pacing according to the inventionthat produces fusion of pacing-induced and intrinsically-activatedventricular depolarization wavefronts results in developed ventricularpressure (dP/dt_(max)) of equal or greater magnitude than bi-ventricularpacing. Left ventricular pacing and fusion within this context means LVstimulation associated with intrinsic conduction via the right bundlebranch. Left ventricular pacing with fusion can be recognized from asurface ECG (or intracardiac electrogram or “EGM”). This implies thatthe degree of fusion is determined by the interval between LV pacing andRV sensing (the LEft ventricular PAcing, Right ventricular Sensinginterval, or “LEPARS interval”). Accordingly, the inventors assert thatthe degree of fusion between LV pacing and intrinsic right bundle branchactivation is determined by the LEPARS interval (i.e., the elapsed timefrom LV stimulation to a sensed, intrinsic right bundle branchactivation of the RV). According to the invention, an optimum value ofthe LEPARS interval, somewhat analogous to the V-V interval oftraditional bi-ventricular pacing, is implemented chronically to providea hemodynamic advantage over RV-only pacing and bi-ventricular pacing.In addition, LV-only pacing according to the invention also requiresless valuable energy compared to bi-ventricular pacing therapy.

In addition, the inventors also found that the LEPARS interval should bemaintained by controlling the operating AV interval for an IPG duringpacing therapy delivery. That is, assuming a static LEPARS interval theoperating AV interval determines whether fusion will be present and themagnitude of the fusion. Assuming that the LV is stimulated beforeintrinsic activation of the LV occurs (via the right bundle branch dueto the LBBB defective conduction condition), three (3) scenarios arise,as depicted in FIG. 5A-D. In FIG. 5A and FIG. 5B, an atrial pace (“AP”)event is followed by a LV pace (“VP”) event at an AV interval of 350 msand 300 ms, respectively. The RV EGMs for these pacing sequences appearsfairly closely aligned with the R-wave of the evoked depolarization andthus, the RV depolarization resulted from intrinsic conduction via theright bundle and no fusion was achieved. In FIG. 5C, the atrial pacingstimulus was followed by LV pacing delivery at 250 ms and LV fusion wasobserved. In FIG. 5D, an AV interval or 200 ms was employed and delayedactivation was observed from the left ventricular stimulus (withoutfusion).

Stated another way, the three scenarios include:

1.) LV fusion can be achieved from LV pacing stimulation and RVintrinsic activation via the right bundle. In this scenario, the LEPARSinterval is shorter than the inter-ventricular conduction time (IVCT).As noted above, the IVCT consists of the interval between LV pacingdelivery and the later arrival of the LV depolarization wavefront at theelectrode disposed in operative electrical communication with the RV.Symbolically, this fusion-generating relationship can be expressed:LEPARS interval <IVCT.

2.) RV fusion can be achieved due to both intrinsic right bundleactivation and RV activation caused by a depolarization wavefront fromLV pacing therapy delivery. Symbolically, this relationship can beexpressed: LEPARS interval≈IVCT.

3. No fusion achieved due to activation at the RV sensing electrode(s)from depolarization wavefronts propagated solely from LV pacingstimulus. In this condition, shortening of the AV interval will notaffect the LEPARS interval. Symbolically, this relationship can beexpressed as: LEPARS interval=IVCT.

From the foregoing, for LV-only pacing a hemodynamic optimum valueexists for the LEPARS interval that depends upon timing of a pair ofdepolarization wavefronts (one evoked in the LV, one intrinsicallypropagated from the atria). Furthermore, hemodynamic parameters (e.g.,dP/dt_(max)) and/or echocardiographic parameters (e.g., aortic VTI, TDI)for minimal LV asynchrony can determine this optimum and the concomitantoptimized LEPARS interval. Once an optimal LEPARS interval has beendetermined, it should be operably programmed in the pacing circuitry.The pacemaker should be able to monitor the LEPARS interval and if theinterval varies, a feedback system should correct this by adaptation ofthe AV interval. FIG. 4 represents the schematic illustration of thisprinciple.

By keeping the LEPARS interval at a constant value by adjusting thevalue of an operating AV delay interval, a pacing system automaticallyadapts to the appropriate AV interval at higher atrial rates (paced orsensed). This implies that even during exercise, when the intrinsic AVshortens, the LEPARS interval is maintained at its optimum value byadaptation of the AV interval.

Before the LEPARS interval is measured the P-P interval should becompared to a mean value of a previous number of cardiac cycles (e.g.,4-, 8-, 16-, 32-cycles). This comparison should avoid ventricular pacingwith an inappropriate AV interval on premature atrial beats or otherarrhythmias causing a sudden variation in intrinsic AV conduction. Inthe event such events occur, the pacing system should revert tobi-ventricular pacing with a relative short AV interval in order tomaintain resynchronization therapy.

The inventors suggest that the LEPARS interval-based pacing therapyshould be applied only in patients with normal intrinsic AV conduction(and LBBB conduction status). It should not be used as a “stand alone”system, but should be a programmable option in bi-ventricular systemsfor selected patients. Furthermore, the LEPARS interval-based pacingtherapy should not be used in patients with irregular heart rhythms,like atrial fibrillation (AF). For example, if AF is detected in apatient with LV pacing using the LEPARS interval-based pacing modality,a mode switch should occur to a non-tracking mode with bi-ventricularpacing.

In the following detailed description, references are made toillustrative embodiments for carrying out an energy efficient, LEPARSinterval-based pacing modality according to the present invention. It isunderstood that other embodiments may be utilized without departing fromthe scope of the invention. For example, the invention is disclosed indetail herein in the context of an intrinsically-based or AV sequential(evoked) uni-ventricular single-chamber pacing system operating in anatrial tracking, demand and/or triggered pacing modes. The presentinvention provides an efficient pacing modality for restoringelectromechanical ventricular synchrony based upon either atrial-pacedor atrial-sensed events particularly for patients having some degree ofeither chronic, acute or paroxysmal ventricular conduction block (e.g.,intraventricular and/or LBBB). Cardiac pacing apparatus according to theinvention are programmable to optionally operate as a dual- ortriple-chamber pacing system having an AV synchronous operating mode forrestoring upper and lower heart chamber synchronization and right andleft atrial and/or ventricular chamber depolarization synchrony. Asystem according to the invention efficiently provides cardiacresynchronization therapy (CRT) with a single ventricular stimulus percardiac cycle. In one embodiment, the inventive pacing system operatesin a VDD or VDD/R operating mode wherein intrinsic atrial events governthe timing of the AV interval (i.e., herein the A-LVP interval).

The present invention provides enhanced hemodynamic performance forpatients having intact nodal conduction but that nevertheless sufferfrom various forms of heart failure, LV asynchrony, LV dysfunction,and/or ventricular conduction abnormalities. Pacing systems according tothe invention can also include rate responsive features andanti-tachyarrhythmia pacing and the like. In addition, a systemaccording to the invention may include cardioversion and/ordefibrillation therapy delivery.

In accordance with an aspect of the present invention, a method andapparatus is provided to restore the normaldepolarization-repolarization cardiac cycle sequence of FIG. 1 and thesynchrony between the RV, septum, and LV that contributes to adequatecardiac output related to the synchronized electromechanical performanceof the RV and LV. The foregoing and other aspects of the invention arerealized through delivery of cardiac pacing stimulation to a more slowlydepolarizing LV that are timed to occur prior to a sensed depolarizationin the RV. As a result of such timing, the LV essentially is“pre-excited” so that the electromechanical performance of RV and LVmerge into a “fusion event.” The amount of temporal pre-excitationprovided depends on a number of factors. For example, physiologicconduction delay from the A-V node through the His-Purkinje fibers,electrical conduction delay for sensing intracardiac events (fromelectrodes through threshold sensing circuitry of a medical device),electrical conduction delay for pacing therapy delivery circuitry,ischemic episodes temporarily tempering conduction pathways, myocardialinfarction(s) zones, all can deleteriously impact cardiac conduction.Because the conduction status of a patient can vary over time and/orvary based on other factors such as heart rate, autonomic tone andmetabolic status, the present invention provides a dynamicallycontrollable pre-excitation pacing modality. For example, based one ormore of several factors, an pre-excitation optimization routine (orsub-routine) can be triggered so that a desired amount of single-chamberfusion-based pacing ensues. Some of the factors include, (i) completionof a pre-set number of cardiac cycles, (ii) pre-set time limit, (iii)loss of capture of the paced ventricle (LV), and/or (iv) physiologicresponse triggers (e.g., systemic or intracardiac pressure fluctuation,heart rate excursion, metabolic demand increase, decrease in heart wallacceleration, intracardiac electrogram morphology or timing, etc.). Thepresent invention inherently compensates for the particular implantationsites of the pace/sense electrode pair operatively coupled to the LVchamber.

FIG. 2 is a schematic representation of an implanted, triple-chambercardiac pacemaker comprising a pacemaker IPG 14 and associated leads 16,32 and 52 in which the present invention may be practiced. The pacemakerIPG 14 is implanted subcutaneously in a patient's body between the skinand the ribs. The three endocardial leads 16,32,52 operatively couplethe IPG 14 with the RA, the RV and the LV, respectively. Each leadincludes at least one electrical conductor and pace/sense electrode, anda remote indifferent can electrode 20 is formed as part of the outersurface of the housing of the IPG 14. As described further below, thepace/sense electrodes and the remote indifferent can electrode 20(IND_CAN electrode) can be selectively employed to provide a number ofunipolar and bipolar pace/sense electrode combinations for pacing andsensing functions, particularly sensing far field signals (e.g. farfield R-waves). The depicted positions in or about the right and leftheart chambers are also merely exemplary. Moreover other leads andpace/sense electrodes may be used instead of the depicted leads andpace/sense electrodes that are adapted to be placed at electrode siteson or in or relative to the RA, LA, RV and LV. In addition, mechanicaland/or metabolic sensors can be deployed independent of, or in tandemwith, one or more of the depicted leads.

The depicted bipolar endocardial RA lead 16 is passed through a veininto the RA chamber of the heart 10, and the distal end of the RA lead16 is attached to the RA wall by an attachment mechanism 17. The bipolarendocardial RA lead 16 is formed with an in-line connector 13 fittinginto a bipolar bore of IPG connector block 12 that is coupled to a pairof electrically insulated conductors within lead body 15 and connectedwith distal tip RA pace/sense electrode 19 and proximal ring RApace/sense electrode 21. Delivery of atrial pace pulses and sensing ofatrial sense events is effected between the distal tip RA pace/senseelectrode 19 and proximal ring RA pace/sense electrode 21, wherein theproximal ring RA pace/sense electrode 21 functions as an indifferentelectrode (IND_RA). Alternatively, a unipolar endocardial RA lead couldbe substituted for the depicted bipolar endocardial RA lead 16 and beemployed with the IND_CAN electrode 20. Or, one of the distal tip RApace/sense electrode 19 and proximal ring RA pace/sense electrode 21 canbe employed with the IND_CAN electrode 20 for unipolar pacing and/orsensing.

Bipolar, endocardial RV lead 32 is passed through the vein and the RAchamber of the heart 10 and into the RV where its distal ring and tip RVpace/sense electrodes 38 and 40 are fixed in place in the apex by aconventional distal attachment mechanism 41. The RV lead 32 is formedwith an in-line connector 34 fitting into a bipolar bore of IPGconnector block 12 that is coupled to a pair of electrically insulatedconductors within lead body 36 and connected with distal tip RVpace/sense electrode 40 and proximal ring RV pace/sense electrode 38,wherein the proximal ring RV pace/sense electrode 38 functions as anindifferent electrode (IND_RV). Alternatively, a unipolar endocardial RVlead could be substituted for the depicted bipolar endocardial RV lead32 and be employed with the IND_CAN electrode 20. Or, one of the distaltip RV pace/sense electrode 40 and proximal ring RV pace/sense electrode38 can be employed with the IND_CAN electrode 20 for unipolar pacingand/or sensing.

In this illustrated embodiment, a bipolar, endocardial coronary sinus(CS) lead 52 is passed through a vein and the RA chamber of the heart10, into the coronary sinus and then inferiorly in a branching vessel ofthe great cardiac vein to extend the proximal and distal LV CSpace/sense electrodes 48 and 50 alongside the LV chamber. The distal endof such a CS lead is advanced through the superior vena cava, the rightatrium, the ostium of the coronary sinus, the coronary sinus, and into acoronary vein descending from the coronary sinus, such as the lateral orposteriolateral vein.

In a four chamber or channel embodiment, LV CS lead 52 bears proximal LACS pace/sense electrodes 28 and 30 positioned along the CS lead body tolie in the larger diameter CS adjacent the LA. Typically, LV CS leadsand LA CS leads do not employ any fixation mechanism and instead rely onthe close confinement within these vessels to maintain the pace/senseelectrode or electrodes at a desired site. The LV CS lead 52 is formedwith a multiple conductor lead body 56 coupled at the proximal endconnector 54 fitting into a bore of IPG connector block 12. A smalldiameter lead body 56 is selected in order to lodge the distal LV CSpace/sense electrode 50 deeply in a vein branching inferiorly from thegreat vein GV.

In this embodiment, the CS lead body 56 would encase four electricallyinsulated lead conductors extending proximally from the more proximal LACS pace/sense electrode(s) and terminating in a dual bipolar connector54. The LV CS lead body would be smaller between the LA CS pace/senseelectrodes 28 and 30 and the LV CS pace/sense electrodes 48 and 50. Itwill be understood that LV CS lead 52 could bear a single LA CSpace/sense electrode 28 and/or a single LV CS pace/sense electrode 50that are paired with the IND_CAN electrode 20 or the ring electrodes 21and 38, respectively for pacing and sensing in the LA and LV,respectively.

Further, FIG. 3 depicts bipolar RA lead 16, bipolar RV lead 32, andbipolar LV CS lead 52 without the LA CS pace/sense electrodes 28 and 30coupled with an IPG circuit 300 having programmable modes and parametersof a bi-ventricular DDDR type known in the pacing art. In addition, atleast one physiologic sensor 41 is depicted operatively coupled to aportion of myocardium and electrically coupled to a sensor signalprocessing circuit 43. In turn the sensor signal processing circuit 43indirectly couples to the timing circuit 330 and via bus 306 tomicrocomputer circuitry 302. The IPG circuit 300 is illustrated in afunctional block diagram divided generally into a microcomputer circuit302 and a pacing circuit 320. The pacing circuit 320 includes thedigital controller/timer circuit 330, the output amplifiers circuit 340,the sense amplifiers circuit 360, the RF telemetry transceiver 322, theactivity sensor circuit 322 as well as a number of other circuits andcomponents described below.

Crystal oscillator circuit 338 provides the basic timing clock for thepacing circuit 320, while battery 318 provides power. Power-on-resetcircuit 336 responds to initial connection of the circuit to the batteryfor defining an initial operating condition and similarly, resets theoperative state of the device in response to detection of a low batterycondition. Reference mode circuit 326 generates stable voltage referenceand currents for the analog circuits within the pacing circuit 320,while analog to digital converter ADC and multiplexer circuit 328digitizes analog signals and voltage to provide real time telemetry if acardiac signals from sense amplifiers 360, for uplink transmission viaRF transmitter and receiver circuit 332. Voltage reference and biascircuit 326, ADC and multiplexer 328, power-on-reset circuit 336 andcrystal oscillator circuit 338 may correspond to any of those presentlyused in current marketed implantable cardiac pacemakers.

If the IPG is programmed to a rate responsive mode, the signals outputby one or more physiologic sensor are employed as a rate controlparameter (RCP) to derive a physiologic escape interval. For example,the escape interval is adjusted proportionally the patient's activitylevel developed in the patient activity sensor (PAS) circuit 322 in thedepicted, exemplary IPG circuit 300. The patient activity sensor 316 iscoupled to the IPG housing and may take the form of a piezoelectriccrystal transducer as is well known in the art and its output signal isprocessed and used as the RCP. Sensor 316 generates electrical signalsin response to sensed physical activity that are processed by activitycircuit 322 and provided to digital controller/timer circuit 330.Activity circuit 332 and associated sensor 316 may correspond to thecircuitry disclosed in U.S. Pat. Nos. 5,052,388 and 4,428,378.Similarly, the present invention may be practiced in conjunction withalternate types of sensors such as oxygenation sensors, pressuresensors, pH sensors and respiration sensors, all well known for use inproviding rate responsive pacing capabilities. Alternately, QT time maybe used as the rate indicating parameter, in which case no extra sensoris required. Similarly, the present invention may also be practiced innon-rate responsive pacemakers.

Data transmission to and from the external programmer is accomplished bymeans of the telemetry antenna 334 and an associated RF transmitter andreceiver 332, which serves both to demodulate received downlinktelemetry and to transmit uplink telemetry. Uplink telemetrycapabilities will typically include the ability to transmit storeddigital information, e.g. operating modes and parameters, EGMhistograms, and other events, as well as real time EGMs of atrial and/orventricular electrical activity and Marker Channel pulses indicating theoccurrence of sensed and paced depolarizations in the atrium andventricle, as are well known in the pacing art.

Microcomputer 302 contains a microprocessor 304 and associated systemclock 308 and on-processor RAM and ROM chips 310 and 312, respectively.In addition, microcomputer circuit 302 includes a separate RAM/ROM chip314 to provide additional memory capacity. Microprocessor 304 normallyoperates in a reduced power consumption mode and is interrupt driven.Microprocessor 304 is awakened in response to defined interrupt events,which may include A-TRIG, RV-TRIG, LV-TRIG signals generated by timersin digital timer/controller circuit 330 and A-EVENT, RV-EVENT, andLV-EVENT signals generated by sense amplifiers circuit 360, amongothers. The specific values of the intervals and delays timed out bydigital controller/timer circuit 330 are controlled by the microcomputercircuit 302 by means of data and control bus 306 from programmed-inparameter values and operating modes. In addition, if programmed tooperate as a rate responsive pacemaker, a timed interrupt, e.g., everycycle or every two seconds, may be provided in order to allow themicroprocessor to analyze the activity sensor data and update the basicA-A, V-A, or V-V escape interval, as applicable. In addition, themicroprocessor 304 may also serve to define variable AV delays and theuni-ventricular, pre-excitation pacing delay intervals (A-LVp) from theactivity sensor data, metabolic sensor(s) and/or mechanical sensor(s).

In one embodiment of the invention, microprocessor 304 is a custommicroprocessor adapted to fetch and execute instructions stored inRAM/ROM unit 314 in a conventional manner. It is contemplated, however,that other implementations may be suitable to practice the presentinvention. For example, an off-the-shelf, commercially availablemicroprocessor or microcontroller, or custom application-specific,hardwired logic, or state-machine type circuit may perform the functionsof microprocessor 304.

Digital controller/timer circuit 330 operates under the general controlof the microcomputer 302 to control timing and other functions withinthe pacing circuit 320 and includes a set of timing and associated logiccircuits of which certain ones pertinent to the present invention aredepicted. The depicted timing circuits include URI/LRI timers 364, V-Vdelay timer 366, intrinsic interval timers 368 for timing elapsedV-EVENT to V-EVENT intervals or V-EVENT to A-EVENT intervals or the V-Vconduction interval, escape interval timers 370 for timing A-A, V-A,and/or V-V pacing escape intervals, an AV delay interval timer 372 fortiming the A-LVp delay (or A-RVp delay) from a preceding A-EVENT orA-TRIG, a post-ventricular timer 374 for timing post-ventricular timeperiods, and a date/time clock 376.

In the present invention, the AV delay interval timer 372 is loaded withan appropriate PEI delay interval for the LV chamber (i.e., either anA-RVP delay or an A-LVp delay as determined by the flow chart depictedat FIG. 4 and FIG. 5) to time-out starting from a preceding A-PACE orA-EVENT. The interval timer 372 times the PEI, and is based on one ormore prior cardiac cycles (or from a data set empirically derived for agiven patient) and does not depend on sensing of a depolarization in theother ventricle (i.e., RV) during pre-excitation fusion-based pacingtherapy delivery according to the present invention.

The post-event timers 374 time out the post-ventricular time periodsfollowing an RV-EVENT or LV-EVENT or a RV-TRIG or LV-TRIG andpost-atrial time periods following an A-EVENT or A-TRIG. The durationsof the post-event time periods may also be selected as programmableparameters stored in the microcomputer 302. The post-ventricular timeperiods include the PVARP, a post-atrial ventricular blanking period(PAVBP), a ventricular blanking period (VBP), and a ventricularrefractory period (VRP). The post-atrial time periods include an atrialrefractory period (ARP) during which an A-EVENT is ignored for thepurpose of resetting any AV delay, and an atrial blanking period (ABP)during which atrial sensing is disabled. It should be noted that thestarting of the post-atrial time periods and the AV delays can becommenced substantially simultaneously with the start or end of eachA-EVENT or A-TRIG or, in the latter case, upon the end of the A-PACEwhich may follow the A-TRIG. Similarly, the starting of thepost-ventricular time periods and the V-A escape interval can becommenced substantially simultaneously with the start or end of theV-EVENT or V-TRIG or, in the latter case, upon the end of the V-PACEwhich may follow the V-TRIG. The microprocessor 304 also optionallycalculates AV delays, post-ventricular time periods, and post-atrialtime periods that vary with the sensor based escape interval establishedin response to the RCP(s) and/or with the intrinsic atrial rate.

The output amplifiers circuit 340 contains a RA pace pulse generator(and a LA pace pulse generator if LA pacing is provided), a RV pacepulse generator, and a LV pace pulse generator or corresponding to anyof those presently employed in commercially marketed cardiac pacemakersproviding atrial and ventricular pacing. In order to trigger generationof an RV-PACE or LV-PACE pulse, digital controller/timer circuit 330generates the RV-TRIG signal at the time-out of the A-RVP delay (in thecase of RV pre-excitation) or the LV-TRIG at the time-out of the A-LVpdelay (in the case of LV pre-excitation) provided by AV delay intervaltimer 372 (or the V-V delay timer 366). Similarly, digitalcontroller/timer circuit 330 generates an RA-TRIG signal that triggersoutput of an RA-PACE pulse (or an LA-TRIG signal that triggers output ofan LA-PACE pulse, if provided) at the end of the V-A escape intervaltimed by escape interval timers 370.

The output amplifiers circuit 340 includes switching circuits forcoupling selected pace electrode pairs from among the lead conductorsand the IND_CAN electrode 20 to the RA pace pulse generator (and LA pacepulse generator if provided), RV pace pulse generator and LV pace pulsegenerator. Pace/sense electrode pair selection and control circuit 350selects lead conductors and associated pace electrode pairs to becoupled with the atrial and ventricular output amplifiers within outputamplifiers circuit 340 for accomplishing RA, LA, RV and LV pacing.

The sense amplifiers circuit 360 contains sense amplifiers correspondingto any of those presently employed in contemporary cardiac pacemakersfor atrial and ventricular pacing and sensing. As noted in theabove-referenced, commonly assigned, '324 patent, it has been common inthe prior art to use very high impedance P-wave and R-wave senseamplifiers to amplify the voltage difference signal which is generatedacross the sense electrode pairs by the passage of cardiacdepolarization wavefronts. The high impedance sense amplifiers use highgain to amplify the low amplitude signals and rely on pass band filters,time domain filtering and amplitude threshold comparison to discriminatea P-wave or R-wave from background electrical noise. Digitalcontroller/timer circuit 330 controls sensitivity settings of the atrialand ventricular sense amplifiers 360.

The sense amplifiers are uncoupled from the sense electrodes during theblanking periods before, during, and after delivery of a pace pulse toany of the pace electrodes of the pacing system to avoid saturation ofthe sense amplifiers. The sense amplifiers circuit 360 includes blankingcircuits for uncoupling the selected pairs of the lead conductors andthe IND_CAN electrode 20 from the inputs of the RA sense amplifier (andLA sense amplifier if provided), RV sense amplifier and LV senseamplifier during the ABP, PVABP and VBP. The sense amplifiers circuit360 also includes switching circuits for coupling selected senseelectrode lead conductors and the IND_CAN electrode 20 to the RA senseamplifier (and LA sense amplifier if provided), RV sense amplifier andLV sense amplifier. Again, sense electrode selection and control circuit350 selects conductors and associated sense electrode pairs to becoupled with the atrial and ventricular sense amplifiers within theoutput amplifiers circuit 340 and sense amplifiers circuit 360 foraccomplishing RA, LA, RV and LV sensing along desired unipolar andbipolar sensing vectors.

Right atrial depolarizations or P-waves in the RA-SENSE signal that aresensed by the RA sense amplifier result in a RA-EVENT signal that iscommunicated to the digital controller/timer circuit 330. Similarly,left atrial depolarizations or P-waves in the LA-SENSE signal that aresensed by the LA sense amplifier, if provided, result in a LA-EVENTsignal that is communicated to the digital controller/timer circuit 330.Ventricular depolarizations or R-waves in the RV-SENSE signal are sensedby a ventricular sense amplifier result in an RV-EVENT signal that iscommunicated to the digital controller/timer circuit 330. Similarly,ventricular depolarizations or R-waves in the LV-SENSE signal are sensedby a ventricular sense amplifier result in an LV-EVENT signal that iscommunicated to the digital controller/timer circuit 330. The RV-EVENT,LV-EVENT, and RA-EVENT, LA-SENSE signals may be refractory ornon-refractory, and can inadvertently be triggered by electrical noisesignals or aberrantly conducted depolarization waves rather than trueR-waves or P-waves.

To simplify the description of FIGS. 4 through 6, it will be assumedthat the following references to an “A-EVENT” and “A-PACE” will be theRA-EVENT and RA-PACE, respectively, if there is no LA pacing or sensingprovided or programmed on, or will be a programmed one of the RA-EVENTor LA-EVENT and RA-PACE or LA-PACE, respectively.

Turning now to FIG. 4, which schematically represents basic principlesof a LEPARS interval-driven pacing modality according to the presentinvention, the operative circuitry 300 of FIG. 3 includes RR intervalcomparator 301, coupled to RV sensing electrodes coupled to lead 32, LVpacing electrodes coupled to LV pacing electrodes coupled to lead 52. Inturn, the RR interval comparator 301 also couples to LV pace (LVp) andRV sense (RVs) interval comparator 303. An output signal from the LVpand RVs interval comparator 303 serves as an input to AV intervaladaptation circuit 305. One of a pair of output signals from the AVinterval adaptation circuit 305 operatively connect to atrial sensingand pacing electrodes that are coupled to atrial lead 16. The other ofthe pair of output signals from the AV interval adaptation circuit 305operatively connects to LVp electrodes coupled to pacing electrodescoupled to the lead 52.

In operation, the RR interval comparator 301 receives cardiac signalsfrom the heart 10 used to calculate, monitor, measure and/or storeinformation related to various intrinsic and evoked cardiac events(e.g., RV and LV activation sequences and/or R-R intervals vianear-field sensing and P-R via near- and far-field sensing and P-P vianear-field sensing). The LVp and RVs interval comparator 303 receivesinformation relating to LEPARS interval (i.e., LV pacing-to-RV-sensing)for one or more cardiac cycles and forwards an output signal relatedthereto to the AV interval adaptation circuit 305. The AV intervaladaptation circuit 305 uses at least the measured LEPARS interval andone or more of the cardiac event information to derive an operating AVinterval (i.e., A-LVp interval) with an essentially constant LEPARSinterval. During an acute procedure, e.g. guided by echo, the optimalLEPARS interval should be determined (e.g., by maximal aortic TDI), thisoptimal LEPARS interval should be stored into the memory of the pulsegenerator (e.g. by programming) and the pulse generator should keep thisinterval essentially constant by varying the A-LVp interval. That is,the pacing electrodes of lead 16 activate the atria and the pacingelectrodes of lead 52 activate the LV upon expiration of the A-LVpinterval.

FIG. 5A-D illustrates four cardiac cycles (A-D) during which pacingoccurred using AV intervals ranging from 350-200 ms, respectively. TheAV intervals are composed of the time period between atrial pacingevents (labeled “AP”) and LV pacing events (labeled “VP”) with theresulting RV EGM waveforms of the evoked responses displayed below thedepicted intervals. In FIG. 5A, a relatively “late-arriving” (i.e., 350ms delayed) VP stimulus aligns closely with the sensed evokeddepolarization in the RV. The depolarization resulted from the intactconduction pathways (AV node, right Bundle of His and right Purkinjesystem) which are denoted as “RB” in FIG. 5. In FIG. 5B, the VP stimulusarrives at the LV 300 ms after the AP event (atrial pacing stimulus) andalso conducts via the RB without causing any fusion depolarization. InFIG. 5C, the VP stimulus arrives at the LV 250 ms after the delivery ofthe atrial pacing stimulus, AP, and causes a fusion depolarization. Asappreciated by those of skill in the art, the interval between thedelivered LV pacing stimulus, VP, and the sensed depolarization (in theRV) constitutes the LEPARS interval. In FIG. 5C, the LEPARS interval isindicated by arrow 570.

FIG. 6 depicts RV and LV QRS complex morphology during RV and LV pacingat AV intervals ranging from 40 ms to 200 ms, at 650-660 and 670-680,respectively. As previously described hereinabove, fusion was notobserved during RV pacing at 40, 120, 140, 160, 180 or 200 ms (denotedby reference numerals 650-660) while fusion was observed during LVpacing at 120, 140, 160 and 180 ms (denoted by reference numerals672,674, 676, 678).

FIG. 7 is a temporal tracing of a surface ECG (denoted by arrow 700), apacing “marker channel” composed of atrial pacing events (AP), LV pacingevents (VP), and select RV sensing events (VR)—because such events aredeemed non-physiologic “refractory” events occurring too soon after theVP events—(denoted by arrow 702), RV EGM (denoted by arrow 704), andresulting LV pressure development expressed as dP/dt_(max) (denoted byarrows 705,706,707). The left-hand set of information corresponds to anA-LVp interval of 200 ms with 10 ms decrements for each other set ofinformation (until the right-hand set of information corresponds to 110ms A-LVp interval). At the relatively shorter AV intervals (denoted byparentheses 707) the LV pacing stimulus is denoted by “VP” and the RVsensed events are denoted as “VR” (708), or ventricular eventsincorrectly deemed non-physiologic due to the temporal proximity to theVP events. In FIG. 7 (at 707), developed pressure increases as the AVintervals are lengthened from 110 ms to 160 ms although no fusiondepolarization have occurred. In contrast, at event 706 with the A-LVpinterval set to 170 ms the “marker channel” (at 702) indicates a singleVP event (and not independently-sensed “VR” event) and developedpressure reached a relative maximum value (972 mmHg/s). In addition, themorphology of the RV EGM 704 corresponding to the 170 ms AV intervalconfirms the presence of fusion depolarization(s). Thus, according tothe invention, a LEPARS interval 711 promoting fusion resulting fromLV-only pacing is defined as the time elapsed from Atrial activation(AP) to sensed RV depolarization (in FIG. 7 concealed as the “VP”event).

FIG. 8 is a graphical depiction 800 comparing percentage increase inpressure development (“% increase dP/dt”) 802 for LV-only pacing therapydelivery at AV₇₅ to 35 patients. Of the 35 patients, 22 developed fusion(804) and 13 that did not develop fusion (806). FIG. 8 thus appears toconfirm the importance of achieving and maintaining ventricular fusionduring LV-only pacing therapy delivery. FIG. 8 also provides support forthe notion that, for at least some percentage of patients, the operatingAV interval (A-LVP interval) may vary over a range of values while stillevoking ventricular fusion. One related aspect of the present inventionprovides slightly greater control freedom during LV-only fusion pacingfor those patients that are able to maintain fusion over a wider rangeof AV intervals. For example, such patients can arguably toleratecontinued LV-only fusion pacing over a greater range of AV intervals.For the purposes of the present invention such patients shall bereferred to as “fusion responders” who can continue to receive LV-onlyfusion pacing therapy over a wider range of heart rates beforeperforming a mode switch to a different pacing modality.

FIG. 9A is a graphical depiction comparing pressure development (dP/dt)for LV-only pacing and bi-ventricular pacing at two different AVintervals (AV₁₀₀ and AV₇₅). In particular, FIG. 9A depicts a comparisonof developing pressure (dP/dt) with bi-ventricular pacing versus LV-onlyventricular pacing at the two AV intervals. Inspection of FIG. 9Aillustrates that when fusion is achieved during LV-only pacing therapyat 904, greater magnitude of maximum pressure development occurs(dP/dt_(max))—of about 979 mmHg/s—than for bi-ventricular pacing 906—ofabout 949 mmHg/s—which is highly significant (p=0.006). As previouslynoted, herein a convention has been employed that at AV₁₀₀, all patientsdeveloped fusion during LV-only pacing. As illustrated in FIG. 8 andFIG. 9B, at an AV interval of 75% of the maximum (AV₇₅), just over 60%of the patients developed fusion depolarizations during LV-only pacingtherapy delivery. That is, as shown by FIGS. 8 and 9B, the inventorsobserved and compared maximum pressure development (dP/dt_(max)) at AV₇₅for patients that achieved fusion 804 and those that did not achievefusion 806. Thus, as shown in FIG. 9B, a higher magnitude pressuredevelopment (dP/dt_(max) 902) was observed for the 22 patients duringLV-only fusion pacing than during bi-ventricular pacing (as depicted at904,906 and 912,914), respectively.

Quantitatively, as shown in FIG. 9A wherein pressure development 902(without distinguishing between patients that developed fusion and thosethat did not), it was observed that 979 mmHg/s was developed duringLV-only fusion pacing according to the invention (at 904) versus about949 mmHg/s for bi-ventricular pacing (at 906). Note that all patientswere paced at AV₁₀₀ in obtaining the data presented at FIG. 9A. Incontrast, at AV₇₅ measured pressure development between the patientsreceiving bi-ventricular pacing (at 910) was about the same as thosereceiving LV-only pacing (at 908). However, as shown in FIG. 9B, whenthe 13 patients who did not achieve LV pacing-based fusion (916,918)—atleast when considered from a hemodynamic perspective—all faredrelatively poorly during LV-only pacing (no fusion) than duringbi-ventricular pacing (919 mmHg/s versus 957 mmHg/s). Thus, achievingand maintaining fusion is paramount to generating superior hemodynamiceffects when delivering LV-only pacing therapy.

The foregoing pressure measurements were obtained using an invasive LVpressure transducer. However, of course a chronically implanted venouspressure transducer (e.g., implanted in the RV) such as the Chronicle®implantable hemodynamic monitor (IHM) can be employed for chronicmeasurement of developing ventricular pressures. In this form of theinvention, a Chronicle IHM and an cardiac IPG can communicate pressureand/or EGM timing information via wireless telemetry so that the IPG canchronically deliver mechanical sensor-confirmed fusion pacing therapy.Of course, the pressure measuring circuitry from the IHM can be includedwithin the housing for an IPG so that a single medical device isutilized to delivery LEPARS interval-based fusion therapy according tothe present invention.

Some of the operating modes of IPG circuit 300 according to the presentinvention are depicted in the flow charts (FIGS. 10-12) and described asfollows. The particular operating mode of the present invention is aprogrammed or hard-wired sub-set of the possible operating modes as alsodescribed below. For convenience, the algorithm of FIGS. 10-12 isdescribed in the context of determining the A-LVp delay intervals tooptimally pace the LV chamber to produce electromechanical fusion withthe corresponding depolarization of the RV chamber. The RV chamberdepolarizes intrinsically so that the pre-excited electromechanicalfusion occurs as between the intrinsically activated RV chamber and theevoked response of the LV chamber. As noted below, the algorithm can beemployed to determine an optimal A-LVP delay that results in ventricularsynchrony (i.e., CRT delivery via a single ventricular pacing stimulus).Of course, the methods according to the present invention are intendedto be stored as executable instructions on any appropriate computerreadable medium although they may be performed manually as well.

FIG. 10 illustrates one embodiment of the present invention wherein theIPG circuit 300 includes a method 400 beginning with step 402 that isperiodically performed to determine the intrinsic ventricular delaybetween the LV and the RV. In step 402, which can be performed on one ormore consecutive cardiac cycles, the physiologic P-R interval ismeasured and stored (for the RV only for patients suffering from LBBB).In step 404 the physiologic P-R interval is decremented to generate apre-excitation pacing interval for the LV chamber (“A-LVp”). Themagnitude that the P-R interval is decremented depends on severalfactors. Some representative factors that can influence the decrement ofthe A-LVp delay include internal circuitry processing delay, location ofsensing electrodes, heart rate, dynamic physiologic conduction status(e.g., due to ischemia, myocardial infarction, conduction fiber orbundle branch defects, etc.). However, the inventors have found that adecrement of approximately 20-40 milliseconds (ms) oftentimes providesapproximately the longest operating A-V interval that maximizes aventricular fusion response and adequate pre-excitation to the LVchamber resulting in electromechanical fusion of both ventricles.Nominally, a decrement of about 30 ms from the P-R interval has providedthe advantages of the present invention. Of course, an iterativesubroutine for decrementing the A-LVp delay can be used and/or aclinical procedure utilized to help narrow a range of prospective valuesfor the magnitude of the decrease in the A-LVp delay. According to thispart of the present invention a series of decrements are implementedover a series of at least several cardiac cycles (as needed for thehemodynamic or contractile response to stabilize). The hemodynamicresponse can be gauged with external or internal sensors (e.g., surfaceECG, intracardiac EGM, internal or endocardial pressure sensor,epicardial accelerometer, arterial flow sensor, etc.). Dopplerechocardiography or ultrasound techniques may also be used to confirmthe appropriate decrement of the A-LVp delay.

In another aspect, a data set is generated for a range of heart ratesthat correspond to measured A-LVp delay intervals. The data may includepaced or intrinsic heart rate data (ppm and bpm, respectively). In thisaspect of the invention, the data set can be employed as a guiding or acontrolling factor during heart rate excursions for continuous deliveryof the single ventricular pre-excitation pacing of the presentinvention. In one form of this aspect of the invention, internalphysiologic sensor data may be used to guiding factor when determiningan appropriate setting for the operating A-LVp interval.

In yet another aspect, a first data set of appropriate values of theA-LVp delay interval are based on evoked response (i.e., wherein theA-EVENT is a pacing event) and a second data set of appropriate valuesof the A-LVp delay interval are based on intrinsic response (i.e.,wherein the A-EVENT is a natural atrial depolarization).

Following the decrementing step 404 the A-LVp delay interval is set andin step 406 LEPARS-based, pre-excitation pacing therapy is delivered. Inaddition, in step 406 (for at least one hemodynamically stable cardiaccycle), the timing of LV pacing and RV sensing events are alsooptionally measured and stored (as the LEPARS interval). Duringmeasurement and storage of the LEPARS interval one or more confirmatorytests should be performed (and/or cardiac data stored) to ensure thatventricular fusion resulted from the single ventricle pacing therapy.Such tests can include temporal ECG or EGM tracings of at least theresulting QRS complexes, acutely invasive or chronic LV or RV fluidpressure measurements, monitor signals from an accelerometer coupled tothe myocardium, and the like.

During delivery of LV pacing according to the invention, the operatingAV delay intervals are used to control, or maintain, the LEPARSinterval. That is, the LEPARS interval should not be allowed to changesubstantially from its original value programmed during ventricularfusion pacing. This aspect of the invention results from the fact thatthe value of IVCT does not change appreciably, even during heart rateexcursions from normal sinus rhythm (e.g., sinus tachycardia). TheLEPARS interval is thus controlled in a simple feedback control loopwherein the LEPARS interval are linked to A-LVp delay intervalmeasurements. The control mechanism can include data sets stored incomputer readable memory (e.g., LUT) and/or can include adynamically-responsive control loop based on current or recently cardiacactivity. As a result, the LEPARS integral can remain relativelyconstant along with the amount of ventricular fusion resulting from thepacing therapy, over a wide variety of conditions.

In the presently illustrated embodiment of the invention, pre-excitationpacing therapy delivery continues until: a pre-set number of cardiaccycles occur, a pre-set time period expires, a loss of capture occurs inthe LV chamber, or a physiologic response trigger event occurs. Thephysiologic response trigger will be described below. With respect tothe other three situations, the number of cardiac cycles or the timeperiod may be set to any clinically appropriate value, given thepatient's physiologic condition (among other factors) before returningto step 402 and (re-)determining the physiologic P-R interval andderiving an operating A-LVp. If a loss of capture in the LV chamber isdetected it could indicate that the LV pacing stimulus is beingdelivered too late (e.g., during the refractory period of the LVchamber) or that the LV pacing electrodes have malfunctioned or becomedislodged. While the process 400 depicted in FIG. 10 reflect that underall the foregoing situations steps 402-406 should be performed followingevents (i)-(iii), the fusion pacing therapy could of course bediscontinued or a mode switch could be performed to another pacingmodality (e.g., an AAI, ADI, AAI/R, ADI/R, double chamber DDD or DDD/R,and the like).

With respect to the physiologic response trigger event(s)—as well asoptionally with respect to condition (iii) wherein loss of capture ofthe LV chamber occurs due to inappropriate timing of the LV pacingstimulus—at step 410 an iterative closed-loop process for determining anappropriate A-LVp interval is performed. In step 410, the A-LVp intervalis directly manipulated from a prior operating value while one or morephysiologic response is monitored and/or measured and stored. Asmentioned above with respect to step 404 with regard to decrementing theintrinsic A-RV interval to generate the operating A-LVp interval, anumber of sensors may be employed. After storing the physiologicresponse data (and corresponding AV delay used during data collection)at step 412 the data is compared and the AV delay corresponding to themost favorable physiologic response is then programmed as the operatingAV delay. The process then proceeds back to step 406 and the LV chamberreceives pre-excitation pacing therapy upon the expiration of thephysiologically-derived AV delay. Of course, of the foregoing steps,steps 402,404,406 may be performed substantially continuously whereinstep 402 (deriving the AV from the intrinsic A-RV interval) is onlyperformed occasionally (e.g., every ten cardiac cycles, during heartrate excursions, etc.). In this form of the invention, the magnitude ofthe decrement of the A-RV can be based upon one or more prior operatingvalues (and several prior operating values, with the most recentreceiving additional statistical weight). In addition to or in lieu ofthe foregoing a look up table (LUT) or other data compilation, asdescribed above, may be utilized to guide or control the derivation ofthe AV value (as described in more detail with respect to FIG. 11).

Now turning to FIG. 11, another embodiment of a method according to thepresent invention is depicted as process 500. To begin process 500, thesteps 502,504,506,508 correspond closely to the corresponding steps ofprocess 400 (FIG. 10) just described. However, at step 510—in the eventthat condition (iv) of step 508 is declared—a data set (or LUT) ofphysiologic responses and corresponding AV (A-LVp) values for a givenpatient is accessed. At step 512 the A-LVp delay is programmed to avalue corresponding to the current physiologic response trigger for thepatient. Then, at step 506, fusion pacing ensues upon expiration of thenewly programmed AV delay interval. A representative physiologicresponse trigger includes an upward or downward heart rate excursion, asensed lack of ventricular synchrony (based on accelerometer, pressure,EGM or other physiologic data signals) and the like.

In FIG. 12, a process 600 for periodically ceasing delivery of thepre-excitation, single ventricular pacing therapy to perform a pacingmode switch to a different form of pre-excitation therapy, ceasingpre-excitation therapy, or allowing normal sinus rhythm to continue(chronically) is illustrated. The process 600 can be implemented as apart of steps 402,502 (or process 400 and 500, respectively) fordetermining the intrinsic A-RV interval or can be performedindependently. In either case, process 600 is designed to help revealimprovement (or decline) of a patient's condition. In the former case,if so-called “reverse remodeling” of the myocardium occurs resulting inreturn of ventricular synchrony and improved hemodynamics and autonomictone, pre-excitation therapy delivery may be temporarily or permanentlyterminated. The patient may, in the best scenario, be relieved of pacingtherapy delivery altogether (programming the pacing circuitry to an ODOmonitoring-only “pacing modality”). Assuming the patient is notchronotropically incompetent, normal sinus rhythm may emerge permanentlyfor all the activities of daily living. Additionally, the process 600may be employed to search for a change in conduction status (e.g.,wherein A-V conduction timing changes, etc.). According to process 600,at step 602 the delivery of LV-only fusion pacing therapy ceases and forat least one cardiac cycle the intrinsic, normal sinus rhythm is allowedto emerge. At step 604 during stable normal sinus rhythmdepolarization(s) of the atria, LV and RV are monitored and, optionallystored in memory (e.g., P-P, P-R, R-R, etc.) and the A-LVP intervalderived. At step 606 LEPARS-based fusion pacing is applied and whenfusion is declared the operative LEPARS interval is stored. At step 608,the process 600 checks to determine if the AV interval has been modified(e.g., due to rate response, programming changes, normal sinus rhythm—ina tracking mode, etc.). In the event that the A-LVP interval has changedfrom a prior operating value, the method proceeds to step 610 whereinLV-only fusion pacing is initiated (or resumed) with a revised A-LVpinterval, but substantially the same LEPARS interval. If the A-LVpinterval has not changed appreciably from a prior operating value thenthe A-LVp LEPARS-based fusion pacing of the present invention is resumedor initiated using the prior operating A-LVP interval and substantiallythe same LEPARS interval. With respect to the magnitude of change to theA-LVp interval required to trigger step 610, as mentioned above athreshold value (or range of values) may be used to trigger step 610depending on whether the patient is deemed a “fusion responder” or not.In contrast, a so-called non-responder patient (or relativelyless-responding patient) can receive LV-only fusion pacing therapy overa relatively small range of A-V interval excursions before expeditiouslymode-switching to a different pacing therapy or ceasing delivery ofpacing therapy.

Of course, certain of the above-described structures, functions andoperations of the pacing systems of the illustrated embodiments are notnecessary to practice the present invention and are included in thedescription simply for completeness of an exemplary embodiment orembodiments. It will also be understood that there may be otherstructures, functions and operations ancillary to the typical operationof an implantable pulse generator that are not disclosed and are notnecessary to the practice of the present invention.

In addition, it will be understood that specifically describedstructures, functions and operations set forth in the above-referencedpatents can be practiced in conjunction with the present invention, butthey are not essential to its practice. It is therefore to beunderstood, that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described withoutactually departing from the spirit and scope of the present invention.

1. A method of LV-only fusion pacing therapy delivery to anon-synchronous pair of ventricles, comprising: a) measuring anintrinsic P-R cardiac interval for a right ventricular (RV) chamber forat least one prior cardiac cycle; b) decrementing the P-R interval toderive a nominal A-LVp interval; c) delivering an LV-only pacing therapyusing the nominal A-LVp interval and d) determining whether ventricularfusion resulted, and in the event that adequate ventricular fusionresulted, then: i) measuring a left ventricular pacing, rightventricular sensing (LEPARS) interval by the amount of time elapsedbetween the delivery of the LV-only pacing therapy and a subsequentsensed depolarization of the RV; and ii) delivering during a subsequentcardiac cycle at least one LV-only pacing therapy pulse to a leftventricular (LV) chamber, wherein said at least one LV-only pacingtherapy pulse is delivered at the expiration of an A-LVp interval thatpreserves heart rate response requirements and substantially preservesthe LEPARS interval; and in the event that ventricular fusion failed toresult, then: modifying the A-LVp interval and repeating step c) throughstep d) above wherein the modified A-LVp interval is implemented in lieuof the nominal A-LVp interval.
 2. A method according to claim 1, whereinthe step of measuring an intrinsic P-R cardiac interval furthercomprises at least one of: calculating an average P-R interval,calculating a weighted average P-R interval, measuring a prior intrinsicP-R interval, looking up a P-R interval correlated to a heart rate,looking up a P-R interval correlated to an activity sensor input,looking up a P-R interval correlated to a minute ventilation value,looking up a P-R interval correlated to a fluid pressure signal, lookingup a P-R interval correlated to a cardiac acceleration signal.
 3. Amethod according to claim 1, further comprising: attempting to detect acardiac arrthymia episode; and in the event the cardiac arrthymia isdetected then either ceasing delivery of the LV-only fusion pacing orperforming a mode switch to a different pacing modality.
 4. A methodaccording to claim 1, wherein said at least one LV-only pacing pulse isdelivered via at least one electrode adapted to be coupled to a portionof the LV chamber.
 5. A method according to claim 4, wherein the step ofdelivering a pre-excitation pulse to said at least one electrode in theLV chamber comprises delivering the pulse to a portion of one of: acoronary sinus, a portion of a great vein, a portion of a vesselbranching from the great vein, an inferolateral cardiac vein.
 6. Amethod according to claim 1, wherein said at least one LV-only pacingtherapy pulse is delivered between a first pacing electrode and a secondpacing electrode, wherein said second pacing electrode comprises one ofthe group: a ring pacing electrode, a pair of electrodes, a can-basedelectrode, a coil electrode, an epicardial electrode, a subcutaneouselectrode, a surface electrode.
 7. A method according to claim 1,wherein the step of measuring the LEPARS interval further comprises: atip and a ring pacing electrode pair configured to operatively couple tothe free wall of the LV chamber for detecting the moment that LV-onlypacing stimulation occurs and a pair of electrodes configured tooperatively couple to the apex portion of the RV chamber to sense thedepolarization of the RV chamber.
 8. A method according to claim 7,wherein at least one of said electrode(s) is adapted to couple to ananterior portion of the free wall of the LV chamber.
 9. A methodaccording to claim 1, wherein said at least one LV-only pacing therapypulse is delivered with at least one electrode adapted to coupleepicardially to the LV chamber.
 10. A method according to claim 1,wherein the subsequent cardiac cycle comprises an immediately subsequentcardiac cycle.
 11. A method according to claim 1, wherein the at leastone prior cardiac cycle comprises an immediately prior cardiac cycle.12. A method according to claim 11, wherein the LEPARS intervalcomprises a discrete range of interval values.
 13. A method according toclaim 1, wherein the at least one prior cardiac cycle comprises at leastthree consecutive, immediately prior, cardiac cycles.
 14. A methodaccording to claim 13, wherein the most recent of the at least threeconsecutive, immediately prior, cardiac cycles is mathematicallyweighted more heavily than the other of said cardiac cycles.
 15. Amethod according to claim 1, further comprising: monitoring aphysiologic cardiac parameter of a patient during delivery of thefusion-based cardiac pacing regimen.
 16. A method according to claim 15,further comprising: comparing the physiologic parameter to a thresholdvalue; and based on the results of the comparison, performing at leastone of: ceasing delivery of the fusion-based cardiac pacing regimen,applying a bi-ventricular pacing regimen on a beat-by-beat basis.
 17. Amethod according to claim 15, wherein the output signal comprises atleast one of: a heart rate output signal, a cardiac pressure outputsignal, a minute ventilation output signal, an activity sensor outputsignal, an acceleration output signal.
 18. A method according to claim17, wherein the plurality of discrete intervals are stored as a data setand wherein each discrete interval of the data set corresponds to amagnitude of the output signal.
 19. An apparatus for delivering LV-onlyfusion-pacing therapy to promote mechanical synchrony between a rightventricular (RV) chamber and a left ventricular (LV) chamber,comprising: means for measuring an intrinsic atrio-ventricular delayinterval for a right ventricular (RV) chamber for at least one priorcardiac cycle; means for delivering during a subsequent cardiac cycle atleast one pacing pulse to a LV chamber, wherein said at least pacingpulse is delivered at the expiration of an A-LVp interval, and whereinthe intrinsic atrio-ventricular (P-R) interval is greater than saidA-LVp interval; and means for measuring and substantially maintaining aleft ventricular pacing, right ventricular sensing (LEPARS) intervalduring said LV-only fusion-pacing therapy delivery over a range ofdifferent paced heart rates.
 20. A method according to claim 19, whereinthe means for measuring the intrinsic atrio-ventricular (P-R) intervalfurther comprises at least one of the following: means for calculatingan average P-R interval, means for calculating a weighted average P-Rinterval, means for measuring a prior intrinsic P-R interval, means forlooking up an P-R interval correlated to a heart rate, means for lookingup an P-R interval correlated to an activity sensor input, means forlooking up an P-R interval correlated to a minute respiration value,means for looking up an P-R interval correlated to a fluid pressuresignal, means for looking up an P-R interval correlated to anacceleration signal.
 21. An apparatus according to claim 19, wherein thecomprises a right ventricle.
 22. An apparatus according to claim 19,wherein said at least one LV-only pacing therapy pulse is delivered viaat least one electrode adapted to be coupled to a portion of the freewall of the LV chamber.
 23. An apparatus according to claim 22, whereinthe step of delivering a pre-excitation pulse to said at least oneelectrode in the LV chamber comprises delivering the pulse to a portionof one of: a coronary sinus, a portion of a great cardiac vein, aportion of a vessel branching from the great cardiac vein, a portion ofan inferolateral cardiac vein.
 24. An apparatus according to claim 19,wherein said at least one LV-only pacing therapy pulse is deliveredbetween: a tip and a ring pacing electrode, a pair of electrodes, a coiland a can-based electrode, a pair of coil electrodes, an epicardialelectrode and a second electrode, or a subcutaneous electrode and thesecond electrode.
 25. An apparatus according to claim 19, wherein themeans for measuring comprises at least one of: a tip and a ring pacingelectrode, a pair of electrodes, a coil and a can-based electrode, apair of coil electrodes, an epicardial electrode and a second electrode,a subcutaneous electrode and the second electrode.
 26. An apparatusaccording to claim 25, wherein at least one of said electrode(s) isadapted to couple to an anterior portion of the left ventricle.
 27. Anapparatus according to claim 19, wherein said at least one LV-onlypacing therapy pulse is delivered with at least one electrode adapted tocouple epicardially to the second-to-depolarize ventricular chamber. 28.An apparatus according to claim 19, wherein the subsequent cardiac cyclecomprises an immediately subsequent cardiac cycle.
 29. An apparatusaccording to claim 19, wherein the at least one prior cardiac cyclecomprises an immediately prior cardiac cycle.
 30. An apparatus accordingto claim 29, wherein the A-LVp interval comprises a discrete intervalamong a plurality of discrete intervals and said plurality of intervalsare correlated to a heart rate, and further comprising: means formonitoring the heart rate of a patient; and means for delivering atleast one ventricular pre-excitation pacing pulse at the expiration ofthe discrete interval and for maintaining the LEPARS interval.
 31. Anapparatus according to claim 30, wherein the heart rate comprises arange of heart rates.
 32. An apparatus according to claim 31, whereinthe plurality of discrete intervals are stored as a data set and whereineach discrete interval corresponds to a range of heart rates.
 33. Anapparatus according to claim 19, wherein the at least one prior cardiaccycle comprises at least three consecutive, immediately prior, cardiaccycles.
 34. An apparatus according to claim 33, wherein the most recentof the at least three consecutive, immediately prior, cardiac cycles ismathematically weighted more heavily than the other said cardiac cycles.35. An apparatus according to claim 19, further comprising: means formonitoring a physiologic cardiac parameter of a patient during deliveryof the fusion-based cardiac pacing regimen.
 36. An apparatus accordingto claim 35, further comprising: means for comparing the physiologicparameter to a threshold value; and at least one of: a. means forceasing delivery of the fusion-based cardiac pacing regimen, b. meansfor applying a bi-ventricular pacing regimen on a beat-by-beat basis, c.means for decrementing the A-LVp delay interval.